Abstract Patients with critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations are commonly complicated with gut mucosal injury and bleeding, but effective therapies to preserve the epithelial integrity are limited to date. Delayed mucosal repair causes disruption of mucosal epithelial integrity in patients with critical surgical stress, thus contributing to the morbidity and mortality. Early rapid epithelial restitution is an important primary repair modality in the gut mucosa and plays a critical role in maintaining mucosal integrity, but the exact mechanism underlying this process remains unclear. Epithelial restitution occurs as a consequence of cell migration over the damaged area after superficial injury, a process that is independent of cell proliferation. Our previous studies have shown the importance of canonical transient receptor potential-1 (TRPC1)-mediated Ca2+ signaling in regulating intestinal epithelial restitution after mucosal injury and that TRPC1 activation is crucial for stimulation of intestinal epithelial cell (IEC) migration after wounding. However, the exact signals initiating TRPC1 channel activation after mucosal injury remain elusive and are the focus of this application. Our preliminary results further indicate that a) intestinal mucosa highly expresses a novel protein caveolin-1 (Cav1); b) Cav1 silencing not only decreases store depletion-induced Ca2+ influx but also represses cell migration in cells overexpressing TRPC1; and c) Cav1 level is tightly regulated by cellular polyamines. Based on these exciting observations, we HYPOTHESIZE that Cav1 plays an important role in promoting gut epithelial restitution after mucosal injury by activating TRPC1 channel activity. Three specific aims are proposed to test the hypothesis: 1) to characterize the functional expression of the Cav1 gene in IECs; 2) to determine if Cav1 activation plays a role in stimulation of IEC migration after mucosal injury in critical surgical conditions; and 3) to define the mechanism underlying Cav1 expression during epithelial restitution, with particularly focusing on cellular polyamines. Completion of this study will provide a fundamental base for development of new therapies to protect the gut mucosa in critical surgical conditions and facilitate repair of damaged mucosa.